The present invention, in some embodiments thereof, relates to plant extracts and, more particularly, but not exclusively, to the use of same for the treatment or prevention of infections including secondary infections of chronic inflammatory diseases.
Atopic dermatitis (AD) is a common chronic inflammatory skin disease, with lifetime prevalence of 10-20% in children, and 1-3% in adults. The incidence of the disease appears to be increasing especially in the developed countries. AD is associated with cutaneous hyper-reactivity to environmental triggers that are innocuous to normal non-atopic individuals and is typified by pruritus, eczematous lesions, xerosis (dry skin), and lichenification of the skin (thickening of the skin and skin marks). AD is often complicated by recurrent infections of skin lesions by bacterial, viral and fungal pathogens (e.g. Staphylococcus aureus colonization takes place in 85-90% of patients with AD). The secondary infection treatments available to date for AD patients do not cure the skin disorder but do control the severity and duration of its symptoms. These treatments include mainly antibiotics to treat secondary infections, topical corticosteroids, and topical calcineurin inhibitors (immuno-suppressant agents). These treatments are not recommended for long-term use, especially for young children, due to their potential side effects.
The underlying biological mechanisms of AD are poorly understood. Several cell types including immune and epidermal cells seem to be involved, including T lymphocytes, mast cells, eosinophils, Langerhans cells and keratinocytes. Other factors, including cytokines and IgE, are also implicated. Many early academic and clinical reports suggest a number of different pathogenic mechanisms. One possible mechanism is an immune defect involving elevation of TH2 cells that interact with Langerhans cells and results in increased production of interleukins IL-4, IL-5, IL-6, IL-10 and IL-13. This leads to increased IgE and decreased gamma interferon levels. Another theory involves the defective barrier function in the stratum corneum leading to the entry of antigens, which results in the production of various inflammatory cytokines.
Recently it was suggested that the high susceptibility for bacterial infection in AD patients is associated with the defective innate defense mechanism, specifically, the low expression of antimicrobial peptides, known as β-defensins Skin biopsies from AD lesions demonstrated deficiently low expression of inflammation induced antimicrobial peptides, thus providing a possible explanation for the susceptibility of patients with AD to skin infections.
β-defensins, including the human β-defensins (hBDs), are natural, small, cationic, amphipathic molecules which are involved in the innate defense mechanism. In the skin, these peptides are secreted by keratinocytes, and have a major role in directly killing the invading microorganisms and modifying inflammatory events. These peptides disrupt the membrane of the target microbe or penetrate the microbial membrane, interfering with intracellular functions. They also display additional roles, such as regulation of inflammatory and immune responses, chemoattracting immune or inflammatory cells to wound or infection/inflammation sites, acceleration of angiogenesis and promotion of wound healing.
Human β-defensin-3 (hBD-3) exhibits potent killing activity against S. aureus and other gram-positive bacteria in addition to activity against gram-negative organisms. Moreover, the antimicrobial activity of hBD-3 is retained at physiologic salt concentrations. Thus, endogenous production of hBD-3 in the epidermis may provide an antimicrobial shield to protect cutaneous tissues from bacterial invasion against pathogens such as S. aureus. 
Regulation of β-defensins expression including, human β-defensin-2 (hBD-2) and human β-defensin-3 (hBD-3) expression, is a complicated mechanism; their expression is elevated by microorganisms, TNF-alpha or IFN-gamma, and is down-regulated by cytokines produced by mast cells and type 2 helper T cells (specifically IL-4 and IL-13).
In vitro studies using primary keratinocytes demonstrated that IL-4 and IL-13 cytokine expression inhibits the expression of β-defensins [Albanesi C. et al., J. Immunol. (2007) 179(2): 984-992]. This inverse correlation was also demonstrated in human skin biopsies [Nomura I. et al., J. Immunol. (2003) 171(6), 3262-3269].
Several herbal extracts that inhibit IL-4 and/or IL-13 expression induced by mast cells and type 2 helper cells have been previously described. These include Gammi-Danguieumja prescription (Rehmannia glutinosa, Angelica gigas, etc.) [Na H J. et al., Inflammation (2004) 28, 291-297], flavonoids (Avanin, Luteolin, Apigenin, Fisetin, etc.) [Kawai, M. et al., Allergology International (2007) 56:113-123], Ailanthus altissima (EAa) [Hua Jin, M. et al., Biol Pham Bult (2006) 29: 884-888], Glycyrrhiza glabra L. (Licorice root) [Ram A et al., Int Immunopharacol. (2006) 6(9):1468-77], Cimicifuga raceomosa [Kim C D et al., Immunopharmacol Immunotoxicol (2004) 26: 299-308] and Cimicifuga racemosa [Kim C D et al., supra].
Herbs that comprise anti-inflammatory and anti-allergic properties have been previously described in the art. These include Sanguisorba officinalis known in Traditional Chinese Medicine to treat eczema and pain in the skin and Silybum marianum previously described to comprise anti-inflammatory properties.
U.S. Pat. No. 6,235,287 discloses diterpenes as well as extracts or concentrates of the plant Curcuma amada containing at least one such diterpene for use as medicaments for immuno-modulation and for the alleviation of pain, and for the treatment or prevention of hypersensitivity diseases and autoimmune disorders.
U.S. Pat. Nos. 6,566,405 and 7,252,845 disclose compositions containing aromatic compounds and terpenoids which are present in and may preferably be derived from the plant Alpinia galanga (Zingiberaceae). These show synergistic effects with respect to immuno-modulation and significantly suppress hypersensitivity reactions. Thus, 6566405 contemplates the use of same for the treatment or prevention of IgE mediated allergic reactions and conditions, such as asthma, allergic rhinitis, a topic eczema or anaphylaxis, and autoimmune disorders, such as Crohn's disease, ulcerative colitis, rheumatoid arthritis or psoriasis, as well as for the alleviation of pain.
U.S. Pat. No. 5,466,452 discloses pharmaceutical herbal compositions for the treatment of skin disorders such as eczema and psoriasis. Specifically U.S. Pat. No. 5,466,452 teaches preparation of an extract or extracts of herbs (e.g. of Potentilla chinensis, Rehmannia glutinosa, Radix paeoniae lactiflorae/veitchii, Dictamnus augustifolia, Glycyrrhiza uralensis, Ledebouriella sesloides, Tribulus terrestris, Lopatheri gracile, Schizonepeta tenuifolia, Akebia trifoliata) which provide an anti-inflammatory agent, an adrenocortical stimulant and a cortisol protecting agent by steam distillation and decoction and then treating the extracts to reduce the polysaccharide and/or sugar content.
U.S. Pat. No. 6,676,975 discloses Chinese herbal compositions for treating eczema and psoriasis. Specifically, U.S. Pat. No. 6,676,975 relates to a material which is suitable for the treatment of atopic disease, non-atopic eczema or psoriasis. The material can be extracted from a freeze-dried decoction of a mixture comprising the following Chinese herbs: Radix Ledebouriella, Fructus Tribuli, Herba Potentilla chinensis, Caulis Clematis armandii, Radix Rehmannia, Radix Glycyrrhiza, Radix Paeonia rubra, Cortex Dictamni radicis, Herba Lopatheri, Spica Schizonepetae. 
U.S. Pat. No. 7,211,567 discloses composition for preventing and treating type I allergy (including atopic dermatitis). The astragalin needed for preparing the compositions taught in U.S. Pat. No. 7,211,567 may be obtained from any astragalin-containing plant e.g. Ailanthus altissima. 
Additional background art includes U.S. Pat. Nos. 6,143,498, 6,329,340, 6,335,318, 6,420,116, 6,911,577 and 7,223,840 and U.S. Patent Application Nos. 20060147442, 20070104722 and 20060036083.